Morpholinoalkanol esters



Patented Jul y 12, 1949 a UNITED STATES. PATENT orrica MORPHOLINOALKANOL Es'rEns Elmore Hathaway Northey and Martin Everett Hultquist, Bound Brook, N. 1., assignors to American Cyanamld Company, New York, N. Y., a corporation of Maine No Drawing. Application April 8, 1942, Serial No. 438,114

iously useful as mydriatics, local anesthetics and I anti-spasmodics.

The compounds of the present invention may be represented by the type formula (M-Alh-Ac in which M is a morpholine radical, Al is an alcohol residue attached to the morpholine ring at the nitrogen atom,'Ac is a carbocyclic-substituted aliphatic acyl group and at is a small whole number. M may be the morpholine ring itself or a substituted morpholine such as 3,5-dimethyl morpholine, 5-ethyl morpholine and the like. Al may be the residue of a saturated or unsaturated alcohol.

Ac may be any diaryl, di-alicyclic or aryl-alicyclic substituted monobasic or polybasic aliphatic acyl group. Typical of the acids with the esters of which the present case is concerned are the arylcyclohexylacetic, diarylpropionic, diarylsuccinic; dicyclohexylacetic acids and'the like, dicyclohexylglycollic, tolllic, anisilic, naphthilic acids and the like. Another typical acid type, with the esters of which the present invention maybe concerned, is the hydroxy acids such as benzilic and the like. These latter esters form the subject matter of our divisional-application Ser. No. 7 ,762, filed Jan. 19, 1949.

These esters in general are oily viscous liquids insoluble in water and soluble in alcohol, acetone and benzene. In general they may be distilled at fairly high temperatures under high vacuum.

They are usually more conveniently. handled in the form of their salts which may be easily prepared since the esters themselves are slightly basic in reaction. The hydrochlorides, for example, are in general white crystalline salts, generally soluble in water and acetone and generally insoluble in ether. Other salts such as the nitrate, sulfate, hydrobromide, citrate, tartrate and the like may be readily prepared if so desired. Quaternary compounds such as the methiodide. ethobromide and the like may also be readily Pre- 2 Claims. (01. 260-247) pared. These quaternary compounds may be readily prepared by treating the base in an alcohol solution with a compound such as methyl iiodide or ethyl bromide and precipitating the salt.

Many of the salts, particularly the hydrochlorides, when in aqueous solution are suitable for use as therapeutics. Many of them are characterized by an extremely low toxicity'as compared with naturally occurring substances such as cocaine or papaverine or with the dialkylaminoalkanol esters of the same acids. For example, in a test on mice injected intra-peritoneally, c0- caine gave an MLD toxicity of about 90 mg. per gram and diethylaminoethyl diphenylacetate about 300 mg. per gram whereas the morpholinoethanol diphenylacetate has the extraordinarily high value of 625 mg. per gram. This lower toxicity is a particular advantage in that it applies whether the material is'being used as a surface 1 therapeutic in the'case of mydriatic use, is taken internally, for example as an anti-spasmodic, or is injected sub-cutaneously as a local anesthetic. This property, therefore, is of special value since the toxic character of naturally occurring compounds used for these purposes was one of the main reasons leading to the extensive research carried out in attempting to find a satisfactory substitute.

The present invention will be more fully illustrated in connection with the following examples which are illustrative and not by way of limitation. All parts are by weight unless otherwise noted.

Example 1 40 parts of fi,fl-diphenyl propionic acid and parts of thionyl chloride were mixed and gently refluxed for V of an hour after which the excess thionyl chloride was distilled off. The residue was dissolved in 400 parts of anhydrous ether and -40 parts of p-morpholino ethanol added thereto fate. The ether was distilled off at atmospheric pressure and the residue distilled at 8 mm pressure at 180-185 C. The ester base was taken up in anhydrous ether and hydrogen chloride gas bubbled through until precipitation stopped. The precipitate was collected and recrystallized from acetone.

Example 2 Mo holinoeth la a-di(aminoto l) propionate m y hydrochloride 24 parts of a,-di-(nitrotolyl) propionyl chloride were dissolved in 35 parts of benzene and 17 /2 parts of N-ethanol morpholine added thereto. The mixture was refluxed for 30 minutes, cooled to 20 C. and the precipitated N-ethanol morpholine hydrochloride removed by filtration. The benzene was distilled from the filtrate and the residue taken up in parts or xylene. To the xylene extract were added 40 parts of iron filings, 10 parts of glacial acetic acid and 40 parts of water and the mixture refluxed for about 2 hours at 92 C. The mixture was filtered, the iron filings washed with xylene and the washings combined with the filtrate and evaporated to dryness. The residue, a very viscous yellow liquid, was then dissolved in 75 parts of acetone and 4 parts or concentrated hydrochloric acid added thereto. A gummy mass separated out which crystallized on stirring with anhydrous ether.

Example 3 Morpholinopropyl diphenylacetate 46 parts of diphenylacetyl chloride were dissolved in 100 parts of benzene. heated to a temperature of reflux and 58 parts or N-n-propanol morpholine were slowly added and the mixture refluxed for 1 additional hour, atter'which the solution was cooled to about 10 C. and the N-npropanol morpholine hydrochloride which precipitated during the reaction was filtered out and the filtrate distilled under reduced pressure to re- 4 move residual benzene. The residue, a slightly yellowish. tinged, viscous oil, was morpholinepropyl diphenylacetate.

Example 4 Morpholinocyclohexyl diphenylacemte To a solution of 46 parts of diphenylacetyl chloride in parts of benzene which was boiling under reflux was added 74 parts of morpholinecyclohexanol over a period of about 30 minutes. After refluxing for 1 hour more the solution was cooled to room temperature, the precipitated N-cyclohexanol morpholine hydrochloride was removed by filtration and the solution distilled to remove the residual benzene. The amber colored residue was morpholinocyclohexyl diphenylacetate.

Example 6 B-N-morpholinoethyl dinaphthylacetste Ha II! To a solution of 66 parts of dinaphthylacetyl chloride in 100 parts of benzene which was boiling under refiiix' was added 52 parts oi morpholinoethanol over a period oi about 30 minutes. After refluxing for 1 hour more the solution was cooled to room temperature, the precipitated N-ethanol morpholine hydrochloride was removed'by filtration and the solution distilled to remove the residualbenzene. The amber colored residue was the p-N-morpholino'ethyl dinaphthylacetate.

While' the preceding examples have been made by the reaction of an acid chloride and-a morpholinoalkanol. the invention is not so limited. In the case of hydroxyacids such as benzilic or dibasic acids such as symmetrical diphen'ylsuccinic acid, the acid chloride can not be prepared. Accordingly, the esters may be best formed by some ype of alcoholysisf Anytype of alcoholysis reaction may be used but' our preferred form is to first form a simple alkyl ester of the acid and then carry out a 'catalyzedester interchange according to the process of Hill and Holmes application Serial No. 431,822 filed February 21, 1942, now Patent No. 2,394,770. Preferably the alcohol which is replaced by the aminoalcohol is continuously removed as it is formed. This procedure will be illustrated by the followin examples.

Example 7 fl-morpholinoethyl benzilate 115 parts of ethyl benzilate, 150 parts fl-4- morpholinoethanol and 0.2 part of metallic sodium were placed ina flask attached to 'a total-reflux variable take-off fractionating column. The pressure was reduced to 100 mm. and heat was applied by an oil bath the temperature of which was slowly raised to 90 C. During three hours of heating 17 parts of ethanol distilled (355 C.). When the distillation of the ethanol became slow, the bath temperature was raised to 120? C. When the vapor temperature indicated distillation of the aminoalcohol the take-off valve was closed and the mixture was refluxed for one hour. At the end of this period the vapor temperature had dropped and two more parts of ethanol were distilled. The remaining aminoalcohol was slowly distilled for three hours. The pressure was then reduced to 20 mm. and the remainder of the aminoalcohol distilled at 66 C. During the reaction the color of the solution changed from'yellow to deep red.

The residue was dissolved in 500 parts of ether,

-washed once with dilute brine, and three timeswith water, dried over sodium sulfate and finally dried over calcium sulfate. 500 parts of a saturated solution of HCl in absolute ether was added and the resulting precipitate filtered. Dry HCl gas was passed into the filtrate to a slight excess and the precipate again filtered. The combined precipitates were washed with cold acetone. The

' targets.

Di- -mcr holinoeth i in..." mi dl in l (B p h ydroeliiorlde p To a solution of 2 parts 0! sodium in 300 parts' of p-morpholinoethanol was added 260 parts of a mixed meso and racemic ethyl ester of diphenylsuccinic acid. The mixture was heated on an oil bath at C. for 48 hours. The excess p-morpholinoethanol was distilled oil and the residue extracted with dilute hydrochloric acid. The

acid extract was washed twice with ether and sodium carbonate until a precipitate formed. The precipitate was filtered out, extracted with ether, the extract added to the filtrate and the combination dried over anhydrous sodium sulfate. The residue was again filtered and the residual ether distilled oil? at atmospheric pressure. The pressure was reduced to 5 mm. and'the traction dis-' tilling from 220-235 C. was collected. .The oily ester base wasdissolved in dry ether and dry hydrogen chloride gas bubbled therethrough until precipitation stopped. Ether was decanted and the gummy residue again treated with dry ether and the ether removed. The residue was treated with acetone, a part being soluble anda part forming a fiocculent precipitate. The mixture was cooled, the precipitate filtered oil, washed with acetone and ether and dried in a vacuum desiccator. The product is a white friable amorphous powder soluble in water and alcohol but insoluble in acetone and ether.

We claim:

1. A chemical compound selected from the group consisting mula and the water-soluble salts oi such esters, in-

which Ac is the residue of a dicarbocycllc-substituted carboxylic acid containing 14-16 carbon atoms and selected from the group consisting of the diphenylpropionic, dicyclohexyiacetic and diphenylsuccinic acids All: is a hydrocarbon residue selected from the group consisting of the -CH2-CH2, CH-.-CH:CH: and

radicals and :c is a small whole number selected from the group consisting of 1 and 2, .1: being 2 only when Ac is the residue 0! diphenylsuccinic acid.

of the esters having the for- 7 2. A chemlcul compglund relegated fig: the BIFIBINOIS m group conslsfln: o! (N-morp ounce Ddlm a phenylsucclnabe o! the formula. y? & m a d in m 5 UNITED STATES PA'I'IN'I'B H Number Rune Dute o L 2,029,962 member May 1;, 2,1 9,805 Wilson Sept. 1 2,246,204 Plnkemelle June 11, 1041 3 2,249,518 Dickey et a July 15, 1941 n, n, FOREIGN PATmu'B E Number Country mm 0 655,404 Germany Jan. 14, 1930 16 658,784 Germany m. 1:, 1m E! 31 857,526 Germany Mar. 7, 1988 OTHER REFERENCES J. Pharmacology, vol. '14. was 290-808. and its water-soluble salts. 20 J. Amer. Chem. 800., vol. 64, Mel 970-073,

J. Amer. Pharmaceutical Assn, vol. 81, pages ELMORE HATHAW AY NORTHEY. 57-59.

MARTIN EVERE'I'I HULTQUIST. J. Amer. Chem. 306., vol. 55, We! 365-370. 

